Human immunodeficiency virus (HIV) infection is associated with a progressive loss of CD4 T cells leading to immunodeficiency and AIDS, and is accompanied by the emergence of numerous opportunistic infections. Oral mucosa is a primary site for secondary infections such as those caused by Epstein Barr Virus (EBV). EBV causes oral hairy leukoplakia (OHL) in immunosuppressed patients and has been shown to actively replicate in the epithelial cells from OHL lesions. In contrast, epithelial cells from patients who are not immunosuppressed do not show active viral infection. This would suggest that HIV infection associated changes in the epithelial microenvironment leads to the reactivation of EBV. Though the advent of anti-retroviral therapy (ART) has had a significant impact on controlling HIV infection and has led to a lower incidence of opportunistic infections, studies have shown that patients who use ART eventually fail to control HIV infection. This failure to control viremia is associated with the reemergence of opportunistic infections such as EBV associated OHL. [unreadable] [unreadable] The exact mechanisms and the factors that lead to active replication of EBV in oral epithelial cells during HIV infection and ART have not been elucidated. The overall objective of this proposal is to delineate the mechanisms of EBV reactivation in the oral mucosa during long-term ART by correlating changes in epithelial cell function and T cell responses with the reactivation of EBV. [unreadable] [unreadable] Rhesus macaques experimentally infected with simian immunodeficiency virus (SIV) and treated with anti-retroviral therapy (PMPA and FTC) will be used in this study. Specific aim 1 will evaluate the effect of ART on host oral epithelial cellular factors and how changes in these factors correlate with reactivation of EBV, and Specific aim 2 will determine the effect of ART on EBV-specific T cell responses with the objective of correlating EBV reactivation with failure of EBV-specific T cell responses. These studies will provide valuable insights into the mechanisms of EBV pathogenesis during long-term ART and help identify novel therapeutic targets to control EBV infection in HIV infected subjects. [unreadable] [unreadable] [unreadable]